Macromolecules such as proteins, peptides and polynucleotides are gaining an ever increasing share of biopharmaceutical research. In contrast to low molecular weight drugs, these large molecules generally have exquisite three-dimensional structures which are critical for their bioactivity. Because of their fragility, the limiting step in the development of new macromolecular drugs often is finding a suitable formulation for storage and delivery. Encapsulation of solid-state protein within polymeric controlled release systems, which offer protection during administration and delivery, is often the only alternative. However, recent research has found even lyophilized proteins are subject to destabilization and degradation dependent on environmental factors such as pH, water content, hydrophobicity and temperature. This research proposes to characterize the physico- chemical environment within a variety of polymers as it relates to protein stability. Intra-polymer pH will be investigated using a range of pH-sensitive fluorescent dyes imaged using laser-scanning confocal microscopy. Similarly, the hydrophobicity within polymers will be probed as a function of monomer composition using a polarity sensitive fluorophore. Finally, we will examine the stability of model proteins loaded within polymeric delivery devices. The results of this project, together with a better understanding of solid-state protein stability, will lead to better protein formulations and, ultimately, increase the utility of controlled release systems for macromolecular pharmaceuticals.